About 2.5 million couples in the US are infertile, representing a major health and social problem. However, our understanding of the underlying genetics of reproduction-gametogenesis in particular- is relative poor. One way to address this issue is to derive mammalian models of reproductive failure, and identify the genes that play roles in the process. This Program Project will use the laboratory mouse, in a forward genetics mutagenesis strategy, to generate the largest collection of mammalian gametogenesis mutants ever established. The value of this resource to the research community will depend largely upon the degree to which the mutations are characterized, the ease with which the mutants can be maintained, and sufficient genetic information to relate mutant phenotypes to particular genes or chromosomal regions. The goals of this project are to genetically map 100 new infertility mutations representing a range of steps in gametogenesis, including stem cell proliferation, meiosis, somatic cell-germ interaction, and post-meiotic development. The linkage of a mutation to molecular markers will facilitate stock maintenance and distribution to colleagues around the world. In addition, a subset of mutations affecting certain aspects of spermatogenesis and oogenesis, selected in consultation with the other Principle Investigators of the Program Project, will be genetically mapped to high resolution as a prelude to positional cloning. Finally, up to ten mutations that primarily affect the regulation of meiosis, recombination, and meiotic chromosome behavior will be positionally cloned to understand the function of the underlying gene products.